PROJECT SUMMARY Lyme disease is the most prevalent arthropod-borne disease in the US with more that 30,000 cases reported to the Centers for Disease Control and Prevention in 2010. The causative agent of the disease is Borrelia burgdorferi (Bb) and is transmitted to humans by the bite of infected ticks. Treatment with antibiotics during the initial stage of the disease is effective, although about 25% of the patients treated with antibiotics continue to suffer from arthritis and other post- Lyme disease syndromes; of those patients treated for neuroborreliosis, many experience lingering symptoms including memory impairment and changes in cognition. Recently, our laboratory has demonstrated that 1) Bb can be detected in the brains of infected rats; 2) Bb can cause neuroinflammatory changes in the brain that recapitulate those seen in human patients and nonhuman primate models; and 3) antibiotic-killed Bb can induce an inflammatory response in the brain, suggesting that dead microorganisms and spirochetal debris that remain after antibiotic treatment can contribute to neural pathology. Our central hypothesis is that Lyme neuroborreliosis results from a sustained Bb-induced neuroinflammatory response in the absence of live microorganisms. We believe that the inflammation and lingering symptoms of neuroborreliosis are due to the persistence of bacterial debris following antibiotic treatment. We have generated several reagents and methodologies to test this hypothesis with 3 Specific Aims. In Specific Aim 1 we will characterize the extent of antibiotic-killed Bb-induced inflammation and persistence of spirochetal debris in the brains of rats. In the second Specific Aim we will quantify neuronal apoptosis and cognitive deficits caused by antibiotic-killed Bb. Finally, in Specific Aim 3 we will determine the signaling pathways mediating Bb-induced neuroinflammation and apoptosis. Our findings will contribute to the knowledge base necessary for the development of intervention strategies for prevention and potentially treatment of post-Lyme disease neurological syndromes.